EP3313397A1 - Inhibiteurs puriques de la phosphatidylinositol 3-kinase delta humaine - Google Patents

Inhibiteurs puriques de la phosphatidylinositol 3-kinase delta humaine

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Publication number
EP3313397A1
EP3313397A1 EP16818503.1A EP16818503A EP3313397A1 EP 3313397 A1 EP3313397 A1 EP 3313397A1 EP 16818503 A EP16818503 A EP 16818503A EP 3313397 A1 EP3313397 A1 EP 3313397A1
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EP
European Patent Office
Prior art keywords
ethyl
purin
amine
methylpyrimidin
propyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP16818503.1A
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German (de)
English (en)
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EP3313397A4 (fr
EP3313397B1 (fr
Inventor
Meredeth Ann MCGOWAN
Hua Zhou
Jason D. Katz
Lihu Yang
Joey L. Methot
Kathryn Ann LIPFORD
Shimin Xu
Ning FU
Guoquan XU
Deqian BIAN
Jianmin Fu
Yabin Li
Kin Chiu Fong
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Merck Sharp and Dohme LLC
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Merck Sharp and Dohme LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • PI3K-delta phosphatidylinositol 3-kinase delta isoform
  • the invention provides methods of using PI3K-delta inhibitory compounds to inhibit PI3K-delta mediated processes in vitro and in vivo.
  • Methods of inhibiting PI3K-delta activity, and methods of treating diseases, such as disorders of immunity and inflammation, in which PI3K-delta plays a role in leukocyte function are disclosed.
  • Methods of using PI3K-delta inhibitory compounds to inhibit cancer cell growth or proliferation are also provided.
  • the methods employ active agents that selectively inhibit PI3K-delta, while not significantly inhibiting activity of other PI3K isoforms.
  • the present invention provides novel compounds which are inhibitors of
  • the invention also provides a method for the treatment and prevention of PI3K-delta -mediated diseases and disorders using the novel compounds, as well as pharmaceutical compositions containing the compounds.
  • the present invention provides compounds of formula I or pharmaceutically acceptable salts or stereoisomers thereof:
  • L is O or NH
  • R 1 is C] -6alkyl, C ⁇ .ghaloalkyl, or a 5- to 6- membered heteroaryl ring, wherein the 5- to 6- membered heteroaryl ring is substituted by 0, 1 , 2, or 3 groups independently selected from fluoro, chloro, Cj .galkyl, and Cj .ghaloalkyl;
  • R 2 is hydrogen or C i -6alkyl
  • R 3 is each independently selected from hydrogen, Ci-i oalkyl, arylCO- 10 alkyl, C3-8
  • R 3 may join together with the carbon to which they are attached to form a 3- to 8-membered ring;
  • R 4 is each independently selected from hydrogen and Ci-ioalkyl, wherein two R 4 may join
  • n 0, 1 , 2, 3, or 4;
  • p 0, 1 , 2, 3, or 4;
  • R 5 is each independently selected from hydrogen, halogen, Ci-ioalkyl, oxo, cyano, Ci-io
  • alkoxyCo-10 alkyl(oxy)o-i Ci_6alkylcarbonyl, Ci_6haloalkyl, cycloalkylCo- 10 alkyl, and -(Ci-iO alky
  • C3_i2heterocycloalkyl is bonded to the illustrated carbonyl via a nitrogen atom
  • Representative compounds of the instant invention include, but are not limited to, the following compounds and their pharmaceutically acceptable salts and their stereoisomers thereof: 8-( 1 -ethyl-5-methyl- 1 H-pyrazol-4-yl)-9-methyl-6-[ 1 -(morpholin-4-ylcarbonyl)propoxy]-9H- purine;
  • the compounds of the present invention include thoses listed below and their pharmaceutically acceptable salts and their stereoisomers thereof:
  • the invention also encompasses pharmaceutical compositions containing a compound of formula I, and methods for treatment or prevention of PI3 -delta mediated diseases using compounds of formula I.
  • One aspect of the present invention is to provide compounds that can inhibit the biological activity of human PI3K-delta.
  • Another aspect of the invention is to provide methods of selectively modulating human PI3K-delta activity and thereby promoting medical treatment of diseases mediated by PI3K-delta dysfunction.
  • the compounds of formula I inhibit PI3K-delta activity in biochemical and cell-based assays and exhibit therapeutic activity in medical conditions in which PI3K-delta activity is excessive or undesirable.
  • Acyl means a -C(0)R radical Where R is optionally substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc.
  • alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbon atoms.
  • Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, iso-, s- and t-butyl, pentyl, hexyl, and the like. Commonly used abbreviations for alkyl groups are used throughout the specification, e.g.
  • methyl may be represented by “Me” or CH 3
  • ethyl may be represented by “Et” or CH2CH3
  • propyl may be represented by “Pr” or CH2CH2CH3
  • butyl may be represented by "Bu” or CH2CH2CH2CH3
  • C 1 -6 alkyl (or “C 1 -C6 alkyl) for example, means linear or branched chain alkyl groups, including all isomers, having the specified number of carbon atoms.
  • Cj -6 alkyl includes all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
  • Cj - 4 alkyl means n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
  • alkylene refers to both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbons, and having two terminal end chain attachments.
  • alkoxy represents a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
  • alkenyl refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and having the indicated number of carbon atoms. Preferably alkenyl contains one carbon to carbon double bond, and up to four nonaromatic carbon-carbon double bonds may be present. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 2-methyl-l-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
  • Alkoxy refers to an alkyl-O- group in which the alkyl group is as described above.
  • Ci- 6alkoxy for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.
  • Alkoxyalkyl refers to an alkyl group as described above in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by alkoxy groups. Examples include CH2OCH3, CH2CH2OCH3 and CH(OCH3)CH3.
  • Aminoalkyl refers to an alkyl group as described above in which one hydrogen atom has been replaced by an amino, monoalkylamino or dialkylamino group. Examples include CH2NH2, CH2CH2NHCH3 and CH(N(CH3)2)CH3.
  • Co-6 alkyl means a direct covalent bond; or when the term appears at the terminus of a substituent, Co-6 alkyl means hydrogen or Cl-6alkyl.
  • an integer defining the presence of a certain number of atoms in a group is equal to zero, it means that the atoms adjacent thereto are connected directly by a bond.
  • T when s is zero.
  • halogen refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro (F), chloro (CI), bromo (Br), and iodo (I)).
  • aryl refers to aromatic mono- and poly-carbocyclic ring systems, wherein the individual carbocyclic rings in the polyring systems are fused or attached to each other via a single bond.
  • Suitable aryl groups include phenyl, naphthyl, 2,3-dihydro-lH-indenyl, and biphenyl.
  • Carboxy refers to the functional group -C(0)OR, for example: ethylcarboxy is - ⁇ phenylcarboxy is - — ; an cyc opropycarboxy s - — O
  • Carboxyalkyl refers to an alkyl group substituted with at least one, specifically one or two, -C(0)OH group(s).
  • carbocycle (and variations thereof such as “carbocyclic” or “carbocyclyl”) as used herein, unless otherwise indicated, refers to (i) a C3 to ⁇ monocyclic, saturated or unsaturated ring or (ii) a C7 to Ci 2 bicyclic saturated or unsaturated ring system. Each ring in (ii) is either independent of, or fused to, the other ring, and each ring is saturated or unsaturated.
  • the carbocycle may be attached to the rest of the molecule at any carbon atom which results in a stable compound.
  • fused bicyclic carbocycles are a subset of the carbocycles; i.e., the term "fused bicyclic carbocycle” generally refers to a C7 to C10 bicyclic ring system in which each ring is saturated or unsaturated and two adjacent carbon atoms are shared by each of the rings in the ring system.
  • a fused bicyclic carbocycle in which one ring is saturated and the other is saturated is a saturated bicyclic ring system.
  • a fused bicyclic carbocycle in which one ring is benzene and the other is saturated is an unsaturated bicyclic ring system.
  • a fused bicyclic carbocycle in which one ring is benzene and the other is unsaturated is an unsaturated ring system.
  • Saturated carbocyclic rings are also referred to as cycloalkyl rings, e.g., cyclopropyl, cyclobutyl, etc.
  • carbocycle is unsubstituted or substituted with Ci-6 alkyl, C ⁇ -6 alkenyl, Ci-6 alkynyl, aryl, halogen, Nl3 ⁇ 4 or OH.
  • a subset of the fused bicyclic unsaturated carbocycles are those bicyclic carbocycles in which one ring is a benzene ring and the other ring is saturated or unsaturated, with attachment via any carbon atom that results in a stable compound. Representative examples of this subset include the following:
  • Cyanoalkyl refers to an alkyl group as described above in which one hydrogen atom has been replaced by a cyano group. Examples include CH2CN, CH2CH2CN and CH(CN)CH3.
  • Cycloalkyl or “C3-12 cycloalkyl” means a carbocyclic ring system having 3 to 12 ring carbon atoms; said ring system may be (a) a monocyclic saturated carbocycle optionally fused to a benzene or a partially unsaturated carbocycle, or (b) a bicyclic saturated carbocycle.
  • the rings are fused across two adjacent ring carbon atoms (e.g., decalin), at one ring carbon atom (e.g., spiro[2.2]pentane), or are bridged groups (e.g., norbornane).
  • Additional examples within the above meaning include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, perhydroindan, decalin, spiro[4.5]decane, spiro[2.5]oxtyl, bicyclo[2.2.2]octane, and the like.
  • C3-8 cycloalkyl (or “C3-C8 cycloalkyl”) means a cyclic ring of an alkane having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl).
  • C3-7 cycloalkyl "C3-6 cycloalkyl”
  • C5-7 cycloalkyl and the like have analogous meanings.
  • Heterocycloalkyl or “C3-12 heterocycloalkyl” refers to a “cycloalkyl” wherein one or more of the carbon atoms are replaced by at least one heteroatom, such as, for example, 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • heteroatom such as, for example, 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • heterocycloalkyls include morpholinyl, pyrazolyl, piperazinyl, azetidinyl, azepanyl,
  • thiomorpholinyl thieno[2,3-c]pyrrolyl, pyrrolidinyl, azaspiro[3.4]octyl, octahydroisoquinolin- 2(lH)-yl, piperidinyl, thiazolidinyl, 1 ,4-oxazepanyl, 8-oxa-5-azaspiro[3.5]non-5-yl, 4-oxa-7- azaspiro[2.5]oxt-7-yl, 5,6-dihydro[l ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl, 1 ,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridin-5-yl, and 2-oxa-5-azabicylco[2.2.1 ]hept-5-yl.
  • Haloalkyl refers to an alkyl group as described above wherein one or more (in particular 1 to 5) hydrogen atoms have been replaced by halogen atoms, with up to complete substitution of all hydrogen atoms with halo groups. for example, includes -CF3, - CF2CF3, -CHFCH3, and the like.
  • Heterocycle represents a monocyclic or bicyclic 3-12 membered ring system in which at least one ring is non-aromatic (saturated or partially unsaturated) and contains at least one heteroatom selected from O, S and N.
  • the second ring may be a heteroaryl, heterocycle or a saturated, partially unsaturated or aromatic carbocycle, and the point(s) of attachment to the rest of the molecule may be on either ring.
  • Heterocyclyl therefore includes heteroaryls, as well as dihydro and tetrahydro analogs thereof. Attachment of a heterocyclyl substituent can occur via a carbon atom or via a heteroatom.
  • saturated heterocyclics form a subset of the heterocycles; i.e., the terms “saturated heterocyclic and heterocycloalkyl” generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is saturated.
  • saturated heterocyclic ring refers to a 3- to 8-membered saturated monocyclic ring or a stable 7- to 12-membered bicyclic ring system which consists of carbon atoms and one or more heteroatoms selected from N, O and S.
  • Representative examples include piperidinyl, piperazinyl, azepanyl, azetidinyl, pyiTolidinyl, pyrazolidinyl, pyrazolyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thieno[2,3-c]pyrrolyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl (or tetrahydrofuranyl), azaspiro[3.4]octyl, octahydroisoquinolin-2(lH)-yl, piperidinyl, thiazolidinyl, 1 ,4-oxazepanyl, 8-oxa-5-azaspiro[3.5]non-5-yl, 4-oxa-7-azaspiro[2.5]oxt-7-yl, and 2-o
  • Heteroaromatics form another subset of the heterocycles; i.e., the term “heteroaromatic” (alternatively “heteroaryl”) generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is an aromatic ring system.
  • heteroaryl generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is an aromatic ring system.
  • heteromatic ring refers a 5- or 6-membered monocyclic aromatic ring or a 7- to 12- membered bicyclic which consists of carbon atoms and one or more heteroatoms selected from N, O and S.
  • the second ring may be a heteroaromatic or an aromatic, saturated, or partially unsatuated carbocycle, and the point(s) of attachment to the rest of the molecule may be on either ring.
  • substituted heteroaiyl rings containing at least one nitrogen atom e.g., pyridine
  • such substitutions can be those resulting in N-oxide formation.
  • heteroaryl examples include, but are not limited to, furanyl, thienyl (or thiophenyl), pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, naphthyridinyl, benzothienyl, benzofuranyl, benzimidazole, benzpyrazolyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolizinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazo
  • bicyclic heterocycles include benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochi manyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl,
  • Heteroalicyclic group refers to a monocyclic or fused ring of 3 to 12 ring atoms containing one, or more heteroatoms in the ring.
  • Spirocyclyl or “spirocyclic ring” refers to a ring originating from a particular annular carbon of another ring.
  • a ring atom of a saturated bridged ring system (rings B and B'), but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spirocyclyl (ring A) attached thereto.
  • a spirocyclyl can be carbocyclic or h
  • all rings of the spirocyclyl system are saturated, such as spiro[2.5]octyl.
  • the individual rings of the spirocyclyl system are selected from both saturated and unstaturated rings.
  • a heteroalicyclic spirocyclyl or "spiroheterocyclic ring,” as used herein, refers to a bicyclic heterocyclic ring as defined above wherein the two rings are joined through a common ring carbon atom.
  • a spiroheterocyclic ring is a 3- to 12-membered ring system containing one to three heteroatoms, e.g., one to two heteroatoms, selected from the group consisting of N and O.
  • Non-limiting examples of spiroheterocyclic rings include azaspiro[2.4]heptyl, l ,9-diazaspiro[5.5]u ⁇ decane; 2,8-diazaspiro[5.5]undecane; 2,8- diazaspiro[4.5]decane; l ,7-diazaspiro[4.4]nonane; l ,7-diazaspiro[4.5]decane; 2,7- diazaspiro[4.5]decane, l -oxa-8-azaspiro[5.5]undecane; 2-oxa-7-azaspiro[4.5]decane; l-oxa-7- azaspiro[4.5]decane; l ,4-dioxa-7-azaspiro[4.5]decane; l ,4-dioxa-8-azaspiro[4.5]decane, 1 ,4- dioxaspiro
  • Non-limiting examples of a carbocyclic spirocyclyl systems comprising include:
  • Hydroalkyl refers to an alkyl group as described above in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by hydroxy groups. Examples include CH 2 OH, Ch CHOH and CHOHCH 3 .
  • Alkylene alkenylene
  • alkynylene alkynylene
  • cycloalkyl ene arylene
  • heteroaiylene heterocyclylene
  • heterocyclylene refer to a divalent radical obtained by the removal of one hydrogen atom from an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl group, respectively, each of which is as defined above.
  • an “unsaturated” ring is a partially or fully unsaturated ring.
  • an “unsaturated monocyclic Cg carbocycle” refers to
  • heterocycle described as containing from “1 to 4 heteroatoms” means the heterocycle can contain 1, 2, 3 or 4 heteroatoms.
  • substituted e.g., as in "aryl which is optionally substituted with one or more substituents "
  • substituents include mono- and poly-substitution by a named substituent to the extent such single and multiple substitution (including multiple substitution at the same site) is chemically allowed.
  • oxy means an oxygen (O) atom.
  • thio means a sulfur (S) atom.
  • Structural representations of compounds having substituents terminating with a methyl group may display the terminal methyl group either using the characters "CH3", e.g. "-CH3" or using a straight line representing the presence of the methyl group, e.g. , i.e.,
  • Ri is a defined variable
  • Rj is a defined variable
  • the value of Ri may differ in each instance in which it occurs
  • the value of Rj may differ in each instance in which it occurs.
  • Rj and Rj are independently selected from the group consisting of methyl, ethyl, propyl and butyl
  • (CRiRj)2 can be
  • R 1 is Cj .ghaloalkyl, or a 5- to 6- membered heteroaryl ring, wherein the 5- to 6- membered heteroaryl ring is substituted by 0, 1 , 2, or 3 groups independently selected from fluoro, chloro, Ci .galkyl, and Cj ⁇ haloalkyl.
  • R 1 is selected from difluoromethyl, trifluoromethyl,
  • R 1 is selected from difluoromethyl, pyrimidinyl, pyridinyl, and pyrazolyl, wherein pyrimidinyl, pyridinyl and pyrazolyl are substituted by 0, 1 , 2, or 3 groups independently selected from fluoro, chloro, methyl, ethyl, and trifluoromethyl.
  • R 1 is selected from difluoromethyl, pyrimidinyl, pyridinyl, and pyrazolyl, wherein pyrimidinyl, and pyrazolyl are substituted by 0, 1 , 2, or 3 groups independently selected from fluoro, chloro, methyl, ethyl, and trifluoromethyl.
  • R 2 is hydrogen or Ci_6alkyl. In a variant of this embodiment, R 2 is selected from methyl, ethyl, propyl, butyl and tert-butyl. In another
  • R is methyl or ethyl. In a variant of this embodiment, R is ethyl.
  • R 2 is hydrogen
  • L is O or NH. In a variant of this embodiment, L is
  • L is NH
  • R 3 is each independently selected from hydrogen, Ci _1 oalkyl, arylCo-10 alkyl, C3.8 cycloalkyl, -(Ci-io alkyl)OH, Ci-io alkoxyCO-10 alkyl, and (Co-10 alkyl)) .2 aminoCo-10 alkyl and wherein two R 3 substituents join together with the carbon to which they are attached to form a propyl or cyclopentyl ring.
  • R 3 is each independently selected from hydrogen, ethyl, methyl, methylphenyl ⁇ benzyl ⁇ , cyclopropyl, acetamide, 2,2-dimethylpropyl, phenyl, isobutyl, propyl, methoxymethyl, hydroxymethyl, cyclopentyl, isopropyl, hydroxyisopropyl,
  • two methyl R 3 substituents join together with the carbon to which they are attached to form a cyclopropyl ring.
  • R 4 is each independently selected from hydrogen and Ci-galkyl, wherein two R 4 may join together with the carbon to which they are attached to form a 3- to 8-membered ring.
  • R 4 is each independently hydrogen, methyl or ethyl. In another embodiment two R 4 join together with the carbon to which they are attached to form a cyclopropyl ring.
  • n is 0, 1 , 2 or 3. In a variant of this embodiment, n is 0, 1 or 2. In yet another embodiment, n is 0 or 1.
  • R 5 is each independently selected from hydrogen, halogen, Cj -galkyl, oxo, cyano, Cj-io alkoxyCo-10 alkyl(oxy)o-i , Ci -6alkylcarbonyl, Ci- 6haloalkyl, cycloalkylCo-10 alkyl, hydroxy, and -(Ci-io alkyl)OH.
  • R 5 is each independently selected from hydroxy, isopropyl, isobutyl, methylcarbonyl, hydrogen, methyl, fluoro, oxo, methoxy, methoxyethyloxy, difluoromethyl, cyano, cyclopropyl, isopropyl, methoxymethyl, and hydroxymethyl.
  • the group — is a C3-i2heterocycloalkyl having at least one nitrogen, wherein the C3_i2heterocycloalkyl is bonded to the illustrated carbonyl in the compound of Formula I via a nitrogen atom.
  • the group is a spiroheterocyclic ring having at least one nitrogen, wherein the spirohetorocyclic ring is bonded to the illustrated carbonyl of the compound of Formula I via a nitrogen atom.
  • the group is selected from morpholinyl, piperidinyl, piperazinyl, azetidinyl, thiomorpholinyl, azepanyl, hexahydro-5H- thieno[2,3-c]pyrrolyl, hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl, pyrrolidinyl,
  • octahydroisoquinolinyl octahydroisoquinolin-2yl, (cis)-octahydroisoquinolin-2yl, 2- azaspiro[3.4]oct-2yl, thiazolidinyl (1 ,3 -thiazolidinyl), 1 ,4-oxazepanyl, 8-oxa-5-azaspiro[3.5]non- 5yl; 4-oxa-7-azaspiro[2.5]oct-7-yl, 5,6-dihydro[l ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl, 1,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl, and 2-oxa-5-azabicyclo[2.2.1 ]hept-5yl.
  • the gro from the compound of Formula I is selected from
  • L is O or NH
  • R 1 is selected from difluoromethyl, pyrimidinyl, pyridinyl, and pyrazolyl, wherein pyrimidinyl, pyridinyl and pyrazolyl are substituted by 0, 1, 2, or 3 groups independently selected from fluoro, chloro, methyl, ethyl, and trifluoromethyl;
  • R 2 is hydrogen or Ci -6alkyl
  • R 3 is each independently selected from hydrogen, ethyl, methyl, methylphenyl ⁇ benzyl ⁇ ,
  • cyclopropyl acetamide, 2,2-dimethylpropyl, phenyl, isobutyl, propyl, methoxymethyl, hydroxymethyl, cyclopentyl, isopropyl, hydroxyisopropyl, dimethylaminoamethyl, 2- methoxypropyl, and methoxyeth-lyl, or two methyl R 3 substituents join together with the carbon to which they are attached to form a cyclopropyl ring.
  • R 4 is each independently selected from hydrogen, methyl and ethyl, or two R 4 join together with the carbon to which they are attached to form a cyclopropyl ring;
  • n 0, or 1;
  • p O, 1, 2, 3, or 4;
  • R 5 is each independently selected from hydroxy, isopropyl, isobutyl, methylcarbonyl, hydrogen, methyl, fluoro, oxo, methoxy, methoxyethyloxy, difluoromethyl, cyano, cyclopropyl, isopropyl, methoxymeth l, and hydrox methyl; wherein the group selected from
  • Patient for the purposes of the present invention includes humans and other animals, particularly mammals and other organisms. Thus the methods are applicable to both human therapy and beterinary applications.
  • “Mammal” means humans and other mammalian animals.
  • “Therapeutically effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that isbeing sought by a researcher, veterinarian, medical doctor or other clinician.
  • treatment includes alleviating, ameliorating, relieving or otherwise reducing the signs and symptoms associated with a disease or disorder.
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of fonnula I, and pharmaceutically acceptable excipients.
  • optionally substituted means "unsubstituted or substituted," and therefore, the generic structural formulas described herein encompasses compounds containing the specified optional substituent as well as compounds that do not contain the optional substituent.
  • each variable is independently defined each time it occurs within the generic structural formula definitions. For example, when there is more than one substituent for aryl/heteroaryl, each substituent is independently selected at each occurrence, and each substituent can be the same or different from the other(s). As another example, for the group -(CR 3 R 3 ) 2 -, each occurrence of the two R 3 groups may be the same or different.
  • each reference to a specific compound of the present invention or a generic fonnula of compounds of the present invention is intended to include the compound(s) as well as phannaceutically acceptable salts thereof.
  • Optical Isomers - Diastereomers - Geometric Isomers - Tautomers Compounds of formula I contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of formula I, either as single species or mixtures thereof.
  • the compounds of the present invention may contain one or more asymmetric centers and can thus occur as "stereoisomers” including racemates and racemic mixtures, enantiomeric mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds.
  • the compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
  • Enantiomers can also be separated by use of chiral HPLC column
  • All stereoisomers for example, geometric isomers, optical isomers and the like
  • of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs
  • those which may exist due to asymmetric carbons on various substituents including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl).
  • stereomeric nomenclature includes "or", for example, (R or S)-8-(l -ethyl-5- methyl- lH-pyrazol-4-yl)-9-methyl-N-(l-methyl-2-mo ⁇ holin-4-yl-2-oxoethyl)-9H-purin-6- amine, the "or” indicates that chiral resolution of racemate into individual enantiomers was accomplished but the actual optical activity of the specific enantiomer was not determined.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • any enantiomer of a compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
  • ammonium, calcium, magnesium, potassium, and sodium salts are particularly preferred.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ '-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.
  • prodrug means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound.
  • the transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
  • mechanisms e.g., by metabolic or chemical processes
  • prodrugs are provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-Cs)alkyl, (C 2 -C] 2 )alkanoyloxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,
  • alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms
  • l-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms
  • 1 -methyl- l-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms
  • N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms
  • 1-(N- (alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C2)alkylamino(C 2 -C3)alkyl (such as ⁇ - dimethylaminoethyl), carbamoyl-(Ci-C 2 )alkyl, N,N-di (Ci-C 2 )alkylcarbamoyl-(Cl-
  • a prodrug can be fonned by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Ci-C6)alkanoyloxymethyl, l-((Ci-C 6 )alkanoyloxy)ethyl, 1 -methyl- l-((Ci- C6)alkanoyloxy)ethyl, (Ci-C 6 )alkoxycarbonyloxymethyl, N-(Ci-C6)alkoxycarbonylaminomethyl, succinoyl, (C] -C6)alkanoyl, a-amino(C)-C 4 )alkanyl, arylacyl and a-aminoacyl, or a-aminoacyl-a- aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(0)(OH) 2 , -
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (Q- Cio)alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural a- aminoacyl,— C(OH)C(0)OY' wherein Y 1 is H, (Ci -C 6 )alkyl or benzyl,— C(OY 2 )Y 3 wherein Y 2 is (C1 -C4) alkyl and Y 3 is (C) -C6)alkyl, carboxy (C) -C6)alkyl, amino(Ci-C4)alkyl or mono-N— or di-N,N-(Ci-C 6 )alkyla
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 0.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • solvates Preparation of solvates is generally known.
  • M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
  • Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001).
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I.
  • different isotopic forms of hydrogen (H) include protium (lH) and deuterium (3 ⁇ 4).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates. Additionally, the present invention is meant to include in compounds of generic Formula I, all suitable replacements of sp3 orbital carbons to sp3 Si as can readily be envisioned by one of ordinary skill in the art. Utilities
  • Compounds of the Invention have activity for PI3K-delta.
  • Compounds of this invention have been tested using the assays described in the Biological Examples and have been determined to be inhibitors of PI3K-delta.
  • Suitable in vitro assays for measuring PI3K-delta activity and the inhibition thereof by compounds are known in the art.
  • Cell-based assays for measurement of in vitro efficacy in treatment of cancer are known in the art.
  • assays are described in the Biological Examples provided herein.
  • Suitable in vivo models for cancer are known to those of ordinary skill in the art. See for example, international patent application published as WO 2012/037226 for further details of in vivo models for prostate adenocarcinoma, glioblastoma, lung carcinoma, and melanoma.
  • Compounds of Formula I may be useful for treating diseases, including autoimmune disorders, inflammatory diseases, and cancers, which are listed below.
  • Cardiac sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma;
  • Lung bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell,
  • adenocarcinoma alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hanlartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous
  • Bone osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges
  • skull skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges
  • meningiosarcoma meningiosarcoma, gliomatosis
  • brain astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma,
  • uterus endometrial carcinoma
  • cervix cervical carcinoma, pre-tumor cervical dysplasia
  • ovaries ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, SertoliLeydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma], fallopian rubes (carcinoma); Hemat
  • malignant melanoma basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands:
  • Autoimmune diseases Hashimoto's thyroiditis, systemic lupus erythematosus (SLE), Goodpasture's syndrome, pemphigus, receptor autoimmune diseases, Basedow's disease (Graves' disease), myasthenia gravis, insulin resistant diseases, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, autoimmune encephalomyelitis, rheumatism, rheumatoid arthritis, scleroderma, mixed connective tissue disease, polymyositis, pernicious anemia, idiopathic Addison's disease, some types of infertility, glomerulonephritis, bullous pemphigus, Sjogren's syndrome, some types of diabetes, adrenergic agent resistance, chronic active hepatitis, primary biliary cirrhosis, endocrine failure, vitiligo, angiitis, post-cardiac surgery syndrome, urticaria, a
  • Inflammatory Diseases asthma, allergic rhinitis, psoriasis, inflammatory arthritis, rheumatoid arthritis, psoriatic arthritis or osteoarthritis, irritable bowel syndrome, ulcerative colitis, Crohn's disease, respiratory allergies (asthma, hay fever, allergic rhinitis) or skin allergies, scleracierma, mycosis fungoides, acute inflammatory responses (such as acute respiratory distress syndrome and ishchemia/reperfusion injury), dermatomyositis, alopecia greata, chronic actinic dermatitis, eczema, Behcet's disease, Pustulosis palmoplanteris, Pyoderma gangrenum, Sezaiy's syndrome, atopic dermatitis, systemic sclerosis, and morphea.
  • the invention provides a method of inhibiting PI3K-delta comprising contacting the PI3K-delta with an effective amount of a compound as disclosed herein.
  • the compounds of the instant invention are selective PI3K-delta inhibitors relative to PI3K-alpha.
  • the determination of relative selectivity for a given compound of PI3K-delta inhibition is defined as the relative ratio of the (PI3K-alpha IC50 value/PDK-delta IC50 value) is at least 2. In yet another embodiment, for a given compound, the relative ratios of the (PI3K-alpha IC50 value/PDK-delta IC50 value) is at least 4.
  • the invention provides a method of treating a PI3K-delta modulated disease comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound as disclosed herein.
  • the invention provides a method of treating cancer disease mediated by PI3K-delta comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound as disclosed herein.
  • the invention also comprises a method of inhibiting PI3K-delta in vivo comprising administering a compound or composition of the invention to a mammal.
  • another aspect of the present invention provides a method for the treatment or prevention of a PI3K-delta mediated disease or disorder comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I.
  • diseases include asthma and rheumatoid arthritis.
  • Another aspect of the present invention provides for the use of a compound of formula I. in the manufacture of a medicament for the treatment or prevention of a PI3K-delta mediated diseases or disorder.
  • prophylactic or therapeutic dose of a compound of formula I will, of course, vary with the nature and the severity of the condition to be treated and with the particular compound of formula I and its route of administration. It will also vary according to a variety of factors including the age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination and response of the individual patient. In general, the daily dose from about 0.001 milligram of active agent per kilogram body weight of a mammal (mg/kg) to about 100 mg/kg, typically, between 0.01 mg to about 10 mg per kg. On the other hand, it may be necessary to use dosages outside these limits in some cases.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration of humans may contain from 0.01 mg to 10 g of active agent compounded with an appropriate and convenient amount of carrier material which may vaiy from about 5 to about 99.95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 0.1 mg to about 0.4 g of an active ingredient, typically 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 400mg, or 500 mg.
  • the final dosage regimen will be determined by the attending physician in view of good medical practice, considering various factors that modify the action of drugs, e.g., the agent's specific activity, the identity and severity of the disease state, the responsiveness of the patient, the age, condition, body weight, sex, and diet of the patient, and the severity of the disease state. Additional factors that can be taken into account include time and frequency of administration, drug combinations, reaction sensitivities, and tolerance/response to therapy. Further refinement of the dosage appropriate for treatment involving any of the formulations mentioned herein is done routinely by the skilled practitioner without undue experimentation, especially in light of the dosage information and assays disclosed, as well as the pharmacokinetic data observed in human clinical trials. Appropriate dosages can be ascertained through use of established assays for determining concentration of the agent in a body fluid or other sample together with dose response data.
  • the frequency of dosing will depend on the pharmacokinetic parameters of the agent and the route of administration. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Accordingly, the pharmaceutical compositions can be administered in a single dose, multiple discrete doses, continuous infusion, sustained release depots, or combinations thereof, as required to maintain desired minimum level of the agent.
  • Short-acting pharmaceutical compositions i.e., short half-life
  • Long acting pharmaceutical compositions might be administered every 3 to 4 days, every week, or once every two weeks.
  • Pumps such as subcutaneous, intraperitoneal, or subdural pumps, can be preferred for continuous infusion.
  • compositions comprising a compound of formula I with a pharmaceutically acceptable earner.
  • compounds of formula I may be administered orally, by inhalation spray, topically, parenterally or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable earners, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection or infusion techniques.
  • the compound of the invention is effective in the treatment of humans.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Patent 4,256,108; 4, 166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water-miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water-miscible solvents such as propylene glycol, PEGs and ethanol
  • an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoole
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in- water emulsion.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butane diol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Dosage forms for inhaled administration may conveniently be formulated as aerosols or dry powders.
  • the active substance is in a particle-size-reduced form, and more preferably the size-reduced form is obtained or obtainable by micronization.
  • the medicinal preparation is adapted for use with a pressurized metered dose inhaler (pMDI) which releases a metered dose of medicine upon each actuation.
  • pMDI pressurized metered dose inhaler
  • the formulation for pMDIs can be in the form of solutions or suspensions in halogenated hydrocarbon propellants.
  • the type of propellant being used in pMDIs is being shifted to hydrofluoroalkanes (HFAs), also known as hydrofluorocarbons (HFCs).
  • HFAs hydrofluoroalkanes
  • HFCs hydrofluorocarbons
  • 1 ,1 ,1 ,2- tetrafluoroethane (HFA 134a) and 1 ,1 , 1 ,2,3 ,3,3-heptafluoropropane (UFA 227) are used in several currently marketed pharmaceutical inhalation products.
  • the composition may include other pharmaceutically acceptable excipients for inhalation use such as ethanol,
  • Pressurized MDIs typically have two components. Firstly, there is a canister component in which the dmg particles are stored under pressure in a suspension or solution form. Secondly, there is a receptacle component used to hold and actuate the canister. Typically, a canister will contain multiple doses of the formulation, although it is possible to have single dose canisters as well.
  • the canister component typically includes a valve outlet from which the contents of the canister can be discharged.
  • Aerosol medication is dispensed from the pMDI by applying a force on the canister component to push it into the receptacle component thereby opening the valve outlet and causing the medication particles to be conveyed from the valve outlet through the receptacle component and discharged from an outlet of the receptacle.
  • the medication particles are "atomized", forming an aerosol. It is intended that the patient coordinate the discharge of aerosolized medication with his or her inhalation, so that the medication particles are entrained in the patient's aspiratory flow and conveyed to the lungs.
  • pMDIs use propellants to pressurize the contents of the canister and to propel the medication particles out of the outlet of the receptacle component.
  • the formulation is provided in a liquid or suspension form, and resides within the container along with the propellant.
  • the propellant can take a variety of forms.
  • the propellant can comprise a compressed gas or liquefied gas.
  • the medicinal preparation is adapted for use with a dry powder inhaler (DPI).
  • DPI dry powder inhaler
  • the inhalation composition suitable for use in DPIs typically comprises particles of the active ingredient and particles of a pharmaceutically acceptable carrier.
  • the particle size of the active material may vary from about 0.1 ⁇ to about 10 ⁇ ; however, for effective delivery to the distal lung, at least 95 percent of the active agent particles are 5 ⁇ or smaller.
  • Each of the active agent can be present in a concentration of 0.01 - 99%. Typically however, each of the active agents is present in a concentration of about 0.05 to 50%, more typically about 0.2 - 20% of the total weight of the composition.
  • the inhalable powder preferably includes pharmaceutically acceptable carrier, which may be composed of any pharmacologically inert material or combination of materials which is acceptable for inhalation.
  • the carrier particles are composed of one or more crystalline sugars; the carrier particles may be composed of one or more sugar alcohols or polyols.
  • the carrier particles are particles of dextrose or lactose, especially lactose.
  • the particle size of the earner particles may range from about 10 microns to about 1000 microns.
  • the particle size of the carrier particles may range from about 20 microns to about 120 microns. In certain other embodiments, the size of at least 90% by weight of the earner particles is less than 1000 microns and preferably lies between 60 microns and 1000 microns. The relatively large size of these carrier particles gives good flow and entrainment characteristics. Where present, the amount of carrier particles will generally be up to 95%, for example, up to 90%, advantageously up to 80% and preferably up to 50% by weight based on the total weight of the powder. The amount of any fine excipient material, if present, may be up to 50% and advantageously up to 30%, especially up to 20%, by weight, based on the total weight of the powder.
  • the powder may optionally contain a performance modifier such as L-leucine or another amino acid, and/or metals salts of stearic acid such as magnesium or calcium stearate.
  • compositions may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.
  • a compound of Formula I is combined in a pharmaceutical combination formulation, or dosing regimen as combination therapy, with one or more other therapeutic agent that has anti-inflammatory or anti-hyperproliferative properties or that is useful for treating an inflammation, immune-response disorder, or hyperproliferative disorder (e.g., cancer).
  • the other therapeutic agent of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of Formula I such that they do not adversely affect each other.
  • Such agents are suitably present in combination in amounts that are effective for the purpose intended.
  • the compound of Formula I may be co-administered with one or more other therapeutic agents for the treatment and prevention of PBKdelta mediated diseases.
  • the present invention provides pharmaceutical compositions for treating PBKdelta mediated diseases comprising a therapeutically effective amount of a compound of fonnula I and one or more other therapeutic agents.
  • a compound of formula I may be combined with other therapeutic agents such as: (1) TNF-a inhibitors such as Remicade® and Enbrel®); (2) non-selective COX-I/COX-2 inhibitors (such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); (3) COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib and etoricoxib); (4) other agents for treatment of TNF-a inhibitors such as Remicade® and Enbrel®); (2) non-selective COX-I/COX-2 inhibitors (such as piroxicam, diclofenac
  • anticholinergic agents such as ipratropium bromide, tiotropium bromide, oxitropium bromide, aclidinium bromide, glycopyrrolate, pirenzepine, and telenzepine;
  • ⁇ -adrenoceptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, fonnoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol, or methylxanthanines including theophylline and aminophylline, sodium
  • IGF-1 insulin-like growth factor type I mimetic
  • IGF-1 insulin-like growth factor type I mimetic
  • IGF-1 insulin-like growth factor type I mimetic
  • IGF-1 insulin-like growth factor type I
  • inhaled glucocorticoid with reduced systemic side effects such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide and mometasone furoate.
  • the compounds of Formula I, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or prodrug thereof may be employed alone or in combination with other therapeutic agents for the treatment of hyperproliferative disorders (e.g., cancer) including standard chemotherapy regimens, and anti-CD20 monoclonal antibodies, rituximab, bendamustine, ofatumumab, fludarabine, lenalidomide, and/or bortezomib.
  • the combination therapy may be administered as a simultaneous or sequential regimen.
  • the combination may be administered in two or more administrations.
  • the combined administration includes coadministration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active therapeutic agents simultaneously exert their biological activities.
  • Gen-1 4,6-dichloropyrimidine-5-amine is elaborated to a common intermediate Gen-1 by addition of an amine (e.g. R 2 -NH 2 ) followed by cyclization.
  • an amine e.g. R 2 -NH 2
  • oxidative cyclization with an aldehyde R'-CHO would yield the corresponding purine.
  • Another cyclization approach would be to perfonn a two-step amide coupling and dehydration using a carboxylic acid R'-C0 2 H.
  • Gen-1 may be elaborated to Gen-2 by addition of the appropriate amine or alcohol nucleophile under basic conditions.
  • reaction with a substituted amino-ester in combination with DIEA under heated conditions would yield the coiTesponding purinyl glycinate derivative.
  • Gen-2 may be elaborated to Gen-3 via the addition of an amine under heated conditions to provide the coiTesponding amide.
  • Gen-2 may be elaborated to Gen-3 via an acid intermediate Gen-4, which can be obtained via basic hydrolysis of ester Gen-2.
  • Gen-4 is then elaborated to Gen-3 via standard amide coupling conditions and the appropriate amine.
  • a protected acid precursor Gen-5 is elaborated to amide Gen-6 via amide coupling conditions.
  • 3-((tert-butoxycarbonyl)amino)butanoic acid can be converted to tert- butyl-(4-oxo-4-(pyrrolidin-l -yl)butan-2-yl)carbamate through the use of amide-coupling reagent COMU, DIEA, and pyrrolidine.
  • the protecting group (PG) may then be removed under standard conditions to provide Gen-7.
  • An example of this is a Boc group removed under acidic conditions.
  • the resulting free amine or alcohol nucleophile may then be added to purine Gen-1 under basic conditions to provide Gen-
  • an intermediate such as Gen-9 may be obtained from 4-chloro-3- nitropyridin-2-amine via amine alkylation and aryl nitro-group reduction.
  • Gen-9 may then undergo a cyclization event, for example with triethoxyethane, to provide Gen-10.
  • Gen-10 may then be elaborated via halogenation and cross-coupling to Gen-11.
  • Gen-11 in turn, can undergo a second cross-coupling with Gen-6 to provide Gen-12.
  • Gen-9 may be elaborated directly to Gen-11. For example, oxidative cyclization of Gen-9 with the appropriate aldehyde would yield Gen-11. 0 nitropyridin-2-amine
  • Step 1 Ethyl-2-(8-( 1 -ethyl-5-methyl- 1 H-pyrazol-4-yl)-9-methyl-9H-purin-6-ylox ylbutanoate
  • Step 2 2-(8-(l -ethyl-5-methyl-l H-pyrazol-4-yl)-9-methyl-9H-purin-6-yloxy)butanoic acid
  • ethyl-2-(8-( l -ethyl-5-methyl- lH-pyrazo]-4-yl)-9-methyl-9H-purin-6- yloxy)butanoate 0.3 g, 0.81 mmol
  • Step 2 2-((8-(l -ethyl-5-methyl-lH-pyrazol-4-vn-9-methyl-9H-purin-6-yl)amino)butanoic acid
  • Compound 1-2 was prepared in an analogous fashion to Example 1-1 using piperidine in place of morpholine in step 3.
  • Compound 1-7 was prepared in an analogous fashion to Example 1-3 using methyl 2- aminopropanoate in the place of methyl 2-aminobutanoate. Chiral resolution of the racemic mixture was achieved via chiral preparative SFC to provide 1-7.
  • Step 2 (R)-2-amino-l -moi , pholino-3-phenylpi pan-l-one
  • Step 1 fert-Butyl l-(4.4-difluoiOpiperidine-l -carbonyl)cyclopropylcarbamate
  • Step 1 (S)-tert-butyl ( 1 -( 1 ,1 -dioxidothiomorpholino)- 1 -oxobutan-2-yl)carbamate
  • the resulting mixture was stirred at RT for 18 h, after which DCM (1 ml) and water ( 1 ml) were added sequentially.
  • the resulting biphasic mixture was passed through a Biotage; Isolute, 120-1905-CG biphasic separatory cartridge to isolate the organic layer, which was then washed with aqueous HC1 (0.5N).
  • the resulting solution was concentrated via
  • Compound 2-2 was prepared in an analogous manner to Example II-l, except that of (S)- 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used in place of (R)-2-(((9H- fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid.
  • Compound 2-6 was prepared in an analogous manner to Example II-3, except that
  • Compound 2-38 was prepared in an analogous fashion to Example II-3 except that octahydropyiTolo[ l ,2-a]pyrazine was used in place of c i-2,6-dimethylmorpholine, TEA was used in place of DIEA, Intermediate III was used in place of Intermediate V, and TFA in DCM was used in place of HCl in 1 ,4-dioxane.
  • Step 1 4-ChloiO-A 2 -ethylpyridine-2,3-diamine
  • Step 4 7-Chloro-3-ethyl-2-(6-(trifluoi methvl)pyridin-3-yl)-3H-imidazo[4,5- ⁇ l pyridine
  • Step 1 fer ⁇ -Butyl-((2S,3R)-l -((cis)-2,6-dimethylmorpholino)-3-methoxy-l -oxobutan-2- yPcarbamate
  • TEA 0.1 mL, 2.1 mmol
  • HATU HATU
  • cw-2,6-dimethylmorpholine 247 mg, 2.14 mmol
  • the resulting mixture was stirred for 1 h under an atmosphere of N 2 .
  • the reaction mixture was then quenched with water (20 mL).
  • the resulting mixture was extracted with DCM (3 x 50 mL), and the combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 S0 4i and filtered.
  • Compound 3-4 was prepared in an analogous fashion to Example III-3, except that 2-((tert- butoxycarbonyl)amino)-2-cyclopropylacetic acid was used in place of (2S,3R)-2-((tert-butoxycarbonyl) amino)-3-methoxybutanoic acid.
  • Chiral resolution of the final compound was achieved via Prep-Chiral HPLC (Column: Chiralpak IA 2x25cm, 5um; Mobile Phase A: Hex-HPLC, Mobile Phase B: IPA-HPLC; Flow rate: 15 mL/min; Gradient: 40 B isocratic over 15 min) to afford compound 3-4 (faster-eluting enantiomer, 8 min).
  • Step 1 Benzyl-3-cyclopropyl-3-hvdiOxyazetidine-l-carboxylate
  • Step 3 (5 ⁇ -?er/-Butyl(l -(3-cyclopi pyl-3-hydiOxyazetidin-l -yl)-l -oxobutan -2- vDcarbamate
  • HATU (1.12 g, 2.95 mmol
  • TEA 1 .03 mL, 7.38 mmol
  • Step 4 (S)-2-Amino-l -(3-cvclopropyl-3-hvdroxyazetidin-l-yl)butan-l-one
  • Step 1 cis-fe -butyl-4-acetyl-3 ,5-dimethylpiperazine- 1 -carboxylate
  • Step 2 1 -cis-2,6-Dimethylpiperazin-l -vPethanone
  • Step 3 tert-B ty ⁇ -(S)- 1 -(cis-4-acetyl-3,5-dimethylpiperazin- 1 -yl)- 1 -oxobutan -2-ylcarbamate
  • Step 4 (SD- 1 -(cis-4-Acetyl-3 ,5-dimethylpiperazin- 1 -yl)-2-aminobutan- 1 -one
  • Step 1 cis-tert-Butyl-3,4.5-trimethylpiperazine-l -carboxylate
  • a solution of cis-/e/'/-butyl-3,5-dimethylpiperazine-l -carboxylate (0.50 g, 2.33 mmol) in DCM (5 mL) were added K 2 C0 3 (0.65 g, 4.67 mmol) and iodomethane (0.15 mL, 2.33 mmol) at RT.
  • the resulting mixture was stirred for 2 h at RT, after which the reaction mixture was diluted with water (1 mL).
  • Step 3 1 ⁇ 2 -Butyl-(,SV 1 -oxo- 1 -(cis-3 A5-trimethylpiperazin- 1 -yl)butan-2 -ylcarbamate
  • Step 4 (S)- 1 -(cis-4-Acetyl-3 ,5-dimethylpiperazin- 1 -yl)-2-aminobutan- 1 -one
  • Step 5 Compound 4-3 To a solution of (5)-2-amino-l -(cis-3,4,5-trimethylpiperazin-l -yl)butan-l -one 2,2,2-trifluoroacetate (120 mg, 0.36 mmol) in i-BuOH (3 mL) were added Intermediate III (0.10 g, 0.36 mmol) and DIEA (0.13 mL, 0.73 mmol) at RT. The resulting solution was stirred for 4 h at 80 °C. The reaction mixture was then cooled to RT concentrated under reduced pressure.
  • Step 1 Dimethyl-2,4-dimethyl-3-oxopentanedioate
  • Step 5 cis-4,4-Difluoi -3,5-dimethylpiperidine
  • Step 7 ( ⁇ -Amino-l -fcis ⁇ -difluoro-S ⁇ S-dimethylpiperidin-l -yDbutan-l -one hydrochloride
  • Step 1 Ethyl-2-(N-benzyl-2-(((benzyloxy)carbonyl)amino)propanamido)acetate
  • Step 2 Ethyl-2-(benzyl(2-(((benzyloxy)carbonyl)amino)pi pyl)amino)acetate
  • Step 4 4-Benzyl- 1 ,6-dimethylpiperazin-2-one
  • Step 6 ?er/-Butyl((2S)-l -(3,4-dimethyl-5-oxopiperazin-l -yl)-l -oxobutan-2-yl) carbamate
  • Step 8 Compounds 4-5 and 4-6
  • Step 1 Benzyl-( 1 -amino-2-methylpi pan-2-yl)carbamate
  • Step 2 Ethyl-2-((2-(((benzyloxy)carbonyl)amino)-2-methylpropyl)amino)acetate
  • Step 3 6,6-Dimethylpiperazin-2-one
  • ethyl 2-((2-(((benzyloxy)carbonyl)amino)-2-methylpropyl)amino)acetate 0.40 g, 1 .30 mmol
  • Pd/C 10% wt., 1.38 g, 1.30 mmol
  • the solution was evacuated and backfilled with hydrogen gas (x3), after which it was stirred for 3 h at RT under an atmosphere of hydrogen (1 atm).
  • the reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure to afford 6,6-dimethylpiperazin -2-one, which was used in the next step without further purification.
  • MS (ESI) calc'd for (C 6 H 13 N 2 0) [M+H] + 129; found 129.
  • Step 4 (S)-tert-Butyl( 1 -(3 ,3-dimethyl-5-oxopiperazin- 1 -vP- 1 -oxobutan-2-yl) carbamate
  • Step 1 3- ethyl-A pyrazin-2-yl)butanehydrazide
  • 2-hydrazinylpyrazine (3.00 g, 27.2 mmol) in ethanol (30 mL) was added 3- methylbutanoic anhydride (7.61 g, 40.9 mmol) at 0 °C, and the resulting mixture was stirred for 1 h at 0 °C.
  • the reaction solution was then quenched b the addition of water (100 mL), and the resulting mixture was extracted with EtOAc (3 x 100 mL).
  • the combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 S0 , and filtered.
  • Step 2 3-Isoburyl-[l ,2,4 ⁇ ]triazoloj ,3-fl1pyrazine
  • Step 3 3-Isobutyl-5,6,7,8-tetrahvdro-
  • Step 4 fer/-Butyl( l -(3-isobutyl-5,6-dihvdro-[l ,2,41triazolo[4,3-a1pyrazin-7(8/ )-yl)-l -oxobutan- 2-yl)carbamate
  • Step 5 2-Amino-l -(3-isobutyl-5,6-dihvdi -rL2,41triazolo[4,3-alpyrazin-7(8H)-yl) butan-l -one 2,2,2-trifluoroacetate
  • Step 1 fcr ⁇ Butyl-3-isobutyryl-4-oxopiperidine-l -carboxylate
  • Step 2 fert-Butyl-3-isopropyl-l -methyl-6, 7-dihvdro-lH-pyrazolor4,3-c]pyridine-5(4H)- carboxylate
  • Step 3 3-Isopropyl-l -methyl-4,5,6,7-tetrahvdiO-l//-pyrazolo[4,3-clPyridine 2,2,2- trifluoroacetate
  • reaction mixture was then quenched by the addition of water (50 mL), and the resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 S0 4 , and filtered.
  • Step 5 2-Aimno-l -(3-isopropyl-l-methyl-6J-dihydi -l -pyrazolo[4,3-clpyridine -5(4/7)- yl butan-l -one 2.2.2-trifluoroacetate
  • the PI3 -Kinase biochemical assays were developed to measure the intrinsic potency and compound dependent inhibition of the alpha, beta, delta, and gamma PI3K isoform enzymes.
  • the native PIP3 produced by PI3-Kinase activity disrupts in a competitive manner the biotin- PIP3 from the PH domain, resulting in the loss of energy transfer (HTRF complex) and a decrease in the signal.
  • the format of this assay is the same for all 4 isoforms of PI3K; the differences lie in the concentration of enzyme used to achieve robust assay window.
  • the alpha, beta, and delta assays are run at 0.5, 1 , and 0.3 nM enzymes and the gamma assay is run at 5 nM enzyme.
  • the ATP concentration is 100 uM in the alpha, beta, and delta assays and 50 uM ATP in the gamma assay. All reactions are run at 5uM PIP2.
  • the PI3-Kinase biochemical assay was optimized using the HTRF kit provided by Upstate (Millipore).
  • the assay kit contains six reagents: 1) 4X Reaction Buffer; 2) native PIP2 (substrate); 3) Stop (EDTA); 4) Detection Mix A (Streptavidin-APC); 5) Detection Mix B (Eu- labeled Anti-GST plus GST-tagged PH-domain); 6) Detection Mix C.
  • PBKinase alpha 14-602, beta 14-603, gamma 14-558 and delta 14-604 from Upstate; Millipore
  • dithiothreitol Sigma, D-5545
  • Adenosine-5' triphosphate InVitrogen, Cat#AS001A
  • native PIP3 PI(3,4,5)P3, diC8, H + , CELLS IGNALS, INC. Cat #907
  • DMSO Sigma, 472301).
  • PBKinase Reaction Buffer is prepared by dilution the stock 1 :4 with de-ionized water. DTT, PIP2 and Biotin-PIP3 were added to 1536 assay plate at a final concentration of 5 mM, 5 mM and 25 nM on the day of use. Enzyme addition and compound pre-incubation are initiated by the addition of 1.25 ul of PI3K (at twice its final concentration) in the IX reaction buffer to all wells using a BioRaptor. Plates are incubated at RT for 15 minutes. Reactions are initiated by addition of 1.25 ul of 2X substrate solution (PIP2 and ATP in IX reaction buffer) using
  • BioRaptor Plates are incubated in humidified chamber at RT for one hour. Reactions are quenched by addition of 0.625 uL of stop solution to all wells using the BioRaptor. The quenched reactions are then processed to detect product formation by adding 0.625 uL of Detection Solution to all wells using the BioRaptor (Detection mix C, Detection Mix A, and Detection Mix B combined together in an 18: 1 : 1 ratio prepared 2 hours prior to use). Following a one hour incubation in the dark, the HTRF signal is measured on the Envision plate reader set for 330nm excitation and dual emission detection at 620nM (Eu) and 665nM (APC).
  • the loss of the HTRF signal is due to the displacement of biotinylated-PIP3 from the PH domain by the PI3K-dependent conversion of PIP2 to PIP3.
  • This loss of signal is nonlinear with respect to both increasing product and time. This non-linear detection will impact accuracy of IC50 calculations; therefore, there is a need for a correction factor to obtain more accurate IC50 values.
  • This correction is derived from a PIP3 standard curve run in a separate assay plate. All data were calculated using the ratio of acceptor (APC) to donor (Europium) fluorescence in each well of the assay plate.
  • PBKdelta IC50 values are listed along with the relative selectivity versus PBKalpha, as well as the physical form of the compound dosed in this assay.
  • the determination of relative selectivity for a given compound is defined as the relative ratio of the (PBK-alphaIC 50 value/PBK-delta IC 50 value).

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Abstract

La présente invention concerne des composés de formule (I) qui sont des inhibiteurs de PI3K-delta et qui sont utiles en tant que tels dans le traitement de maladies médiées par PI3K-delta, telles que l'inflammation, l'asthme, la BPCO et le cancer.
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